Safety and tolerability of a 5 mg starting dose of vericiguat among patients with heart failure: The VELOCITY study

Aims: In clinical practice, simplifying the number of medication titration steps while maintaining safety may improve the likelihood of patients with heart failure (HF) achieving target doses of guideline-directed medical therapy (GDMT). The VELOCITY study examined whether removing the 2.5 mg initiation step for vericiguat, and instead initiating therapy at 5 mg daily, would be safe and well-tolerated. Methods and results: VELOCITY was a prospective, 2-week, single-arm, open-label phase 2b study that enrolled patients with chronic HF with ejection fraction <45%, with or without a recent (≤6 or >6 months) worsening HF (WHF) event. Patients with systolic blood pressure <100 mmHg, recent symptomatic hypotension, and recent change in background GDMT or diuretic dosing were excluded. Participants were initiated on vericiguat 5 mg daily and followed for the primary endpoint, defined as completion of 2-week period with maximum 1-day interruption and without moderate to severe symptomatic hypotension between Visit 1 (Day 1) and Visit 2 (Day 14). Among 106 study patients (mean age 67 years, 28% female), 50% had recent WHF. Background GDMT included 54% prescribed angiotensin receptor–neprilysin inhibitors and 81% prescribed sodium–glucose cotransporter 2 inhibitors. The primary tolerability endpoint was met in 93.4% of patients, including 90.6% of patients in the WHF group and 96.2% of patients in the non-WHF group. Tolerability of initiating vericiguat 5 mg was generally consistent across the pre-specified sensitivity and secondary endpoints. When comparing patients initiating vericiguat 2.5 mg daily in VICTORIA with those starting vericiguat 5 mg daily in VELOCITY, the proportion meeting the VELOCITY primary tolerability endpoint was 97.2% in VICTORIA versus 93.4% in VELOCITY. Conclusions: In the prospective VELOCITY study of patients with chronic HF with ejection fraction <45% who were well-treated with background GDMT, >9 of 10 patients safely tolerated initiation of vericiguat at the 5 mg/day dose. Findings were generally consistent regardless of recent history of WHF. In the context of safety and tolerability data from prior vericiguat studies, VELOCITY supports a potential update in clinical guidance to include a 5 mg starting dose of vericiguat among patients without recent hypotension. Clinical Trials Registration: ClinicalTrials.gov NCT06195930.